Derivatives of 3-benzoyl-2-({62 -hydroxyphenethylamino)-propionitrile

ABSTRACT

The present invention relates to new pharmacologically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula   AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, WHEREIN R1 stands for a member selected from the group consisting of CN, -CONH2, -COOH, -COONa and -COOK, R2 stands for a member selected from the group consisting of   X stands for alkylene having 1 to 4 carbon atoms, Y stands for a member selected from the group consisting of -OCO- and -CO-NH-, R3 and R4 each stand for a member selected from the group consisting of hydrogen and alkyl having 1 to 6 carbon atoms, R5 stands for a member selected from the group consisting of hydrogen and -OH, the nucleus I may have 1 to 3 alkoxy, halogen, alkyl or nitro substituents, THE NUCLEUS II may have 1 to 3 alkoxy, halogen or alkyl substituents, THE NUCLEUS III may be substituted by 1 to 3 methoxy groups and to processes for producing said ketone derivatives.

United States Patent l l Raabe et al.

[ Nov. 5, 1974 DERIVATIVES OF 3-BENZOYL-2-( B-HYDROXYPHENE- THYLAMlNO)-PROPIONITRILE [73] Assignee: Cassella Farbwerke mainkur Aktiengesellschaft, Frankfurt (Main)-Fechenheim, Germany 22 Filed: Mar. 29, 1972 21 Appl. No.: 239,359

[30] Foreign Application Priority Data Apr. 2, l97l Germany 2116293 [52] US. CL... 260/465 E, 260/268 C, 260/268 CN,

260/471 A, 260/518 A, 260/519, 260/559 A, 424/250, 424/304, 424/309, 424/319, 424/324 [51] Int. Cl. C070 121/50 [58] Field of Search 260/465 E [56] References Cited UNITED STATES PATENTS 3,225,095 l2/l965 Thiele 260/465 X 3,646,145 2/1972 Thiele 260/465 X Primary Examiner-Lewis Gotts Assistant Examiner-Dolph H. Torrence Attorney, Agent, or FirmFrancis M. Crawford [57] ABSTRACT The present invention relates to new pharmacologically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula and their pharmaceutically acceptable acid addition salts, wherein R stands for a member selected from the group consisting of CN, CONHg, COOH. COONa and COOK, R stands for a member selected from the group consisting of and X stands for alkylene having I to 4, carbon atoms, Y stands for a member selected from the group consisting of OCO- and CONH,

R 3 and R each stand for a member selected from the group consisting of hydrogen and alkyl having I to 6 carbon atoms,

R, stands for a member selected from the group consisting of hydrogen and OH,

the nucleus 1 may have 1 to 3 alkoxy, halogen,

alkyl or nitro substituents,

the nucleus 11 may have 1 to 3 alkoxy, halogen or alkyl substituents,

the nucleus III may be substituted by 1 to 3 methoxy groups and to processes for producing said ketone derivatives.

6 Claims, No Drawings DERIVATIVES OF 3-BENZOYL-2-(B-HYDROXYPHENE- THYLAMINO)-PROPIONITRILE The present invention relates to new, pharmacologically valuable ketone derivatives of the general formula @-COCH -?HR I wherein R stands for CN, CONI-I COOH, COONa or COOK,

R stands for -N N X Y -@-or f CH 1 X stands for alkylene having 1 to 4 carbon atoms,

Y stands for OCO- or CONH R and R each stand for hydrogen or alkyl having up to 6 carbon atoms, and

R stands for hydrogen, or OH,

the nucleus I may have I to 3 alkoxy, halogen, alkyl or nitro substituents,

the nucleus Il may have 1 to 3 alkoxy, halogen or alkyl substituents, and

the nucleus III may be substituted by l to 3 methoxy groups.

The symbols R,, R R R R X and Y used in the above formula have the same meanings throughout the specification, and nuclei indexed I, II or III may be substituted as defined above.

The compounds of general formula I contain at least one basic nitrogen atom and may consequently form or be formed as salts, in particular hydrohalides, and the invention extends to such acid addition salts, where 'pharmaceutically acceptable.

Preferred halogen substituents for the nucleus I and- /or the nucleus II are fluorine, chlorine and bromine. Preferred alkyl substituents of the nucleus I and of the nucleus II contain 1 to 8 carbon atoms. Preferred alkoxy substuents are methoxy groups.

The compounds of formula I may be prepared, for

example, by the addition of amines of the general for- 50 mula to compounds of the general formula and Y represents the OCO group, so that they have the general formula to compounds of the general formula III followed by esterification of the adducts with benzoic acid derivatives of the general formula 0 wherein Z stands for a halogen atom or the radical 5 Those compounds of formula I in which R, stands for a nitrile group may also be prepared by addition of' HCN to vinylogous amines of the general formula I c0 CH CH n VII.

Those compounds of formula I in which R stands for a COOH, COONa or COOK group may also be prepared by acid s'aponification of the corresponding nitriles VIII according to the following reaction:

- VIII CODE or, in some cases, by diazotation of the corresponding carbonamides X according to the following reaction equation .I v @CO- CH -CIEH-R CODE Wherein R, is COONa or COOK, the carboxyl group in compound IX is converted to the corresponding sodium or potassium carboxylate.

Such of the starting materials 11] as are not yet destance with concentrated sulfuric acid according to the scribed in the literature may be prepared by known following reaction scheme:

methods. 7 G3 I hus, compounds of formula III, wherein R repre- CO CH=CH CEN I sents the nltrile group, may be prepared by a method 9 analogous to that described by A. Nesmeyanov (Dokl. XIX Akad. Nauk SSSR, 115, page 315 (1957)), by reacting compounds of the general formula 10 XX @co cH CH c1 XI g Initial compounds of formula III wherein R reprei sents the COOH group may be prepared either by th m th l d Subsequent r ti with diazotation of the corresponding carbonamides XX ac- KCN: cording to the following reaction scheme N (CH CO-CH=CHC1 3 3 5 COCH=CH-N (CH 3 XI I XIII KCN @-CO-CH=CHN (CH3 3 5 -COCH=CH-CN XI II XIV The chlorides Xl necessary for this purpose. may be 7 7 prepared, as far as they are not yet described in literature, according to known per se methods. The simplest method for the preparation of the chlorides Xlconsists XX 1n the addit on, in the presenee of Friedel-Crafts-type CO CH=CH CQOH catalysts, of suitable acid chlorides XV on acetylene according to the following reaction equation: XXI

l or directly by saponification of the nitriles XIX accord- CO-Cl HC=CH" 7 ing to the following scheme XXI in the ease of certain acid chlorides this reaction is or y {action of malelc atfid alrllllydrride with l difficult to carry out, for instance if the nucleus I bears p l benzene derlvflllves under the condltlons of one or more alkoxy groups. In this case the correspondthe pnedel-crafts reactlon ing acetophenones XVI are subjected to an alkaline ester condensation with formiates. From the sodium or potassium salts XVII of the benzoylvinylalcohols thus 3 1 obtained it is possible to prepare by way of hydrolysis the benzoylvinylalcohols XVlll which on their part may be converted with suitable chlorinating agents, such as thionylchloride or phosphortrichloride, to the benzoyl- Co'cH=CHcOOH vinylehlorides XI: XXI

XVI XVII XVI I I XI Initial compounds of formula III wherein R repre- The compounds of general formula I of the present sents the CO-NH group may be prepared by partial invention are valuable pharmaceuticals. Theyei rert, essaponification of the corresponding nitriles, for inpecially where R meansCN,for instance,adist1nct dilatory action on the cerebral vessels and are, in this respect, far superior to other known substances of this kind. The compounds of the present invention and their pharmaceutically acceptable salts may be employed together with pharamaceutically acceptable diluents or carriers for the preparation of pharmaceutical formulations such as tablets, dragees, suppositories, capsules, solutions, suspensions or emulsions.

These pharmaceutical preparations may also contain other therapeutically active substances.

Pharmacological investigations of the dilatory action of compounds according to the invention on the cerebral vessels were carried out in anaesthetized dogs by observing the changes in blood flow and oxygen tension menten in Forschung und Klinik, Georg Thieme Verlag Stuttgart, 1963). Besides the heat-conductive probe, a teflon-coated multiwire-platinum electrode supplied by Eschweiler of Kiel, was applied to the brain for measuring the local oxygen tension (Literature consulted: D.W. LUBBERS Methods of measuring oxygen tensions of blood and organ surfaces in D1. PAYNE and D.W. HILL Oxygen Measurements in Blood and Tissues and their Significance J. and A. Churchill Ltd., London 1966)). Blood pressure was measured in the femoral artery with the aid of an electromanometer of the STATHAM straingauge type.

The following table gives the results of the above pharmacological investigations.

Maximal change Maximal change in Maximal change of Preparation LD 50 Dosage of the cerebral oxygen tension of the blood pressure g./kg. mg./kg. blood flow the brain-surface (systolic/diastolic) mouse in% in min. in% in minutes in% in minutes 3-(3'-methoxybenzoy1)-2- 1.0 5.0 +153 45 +32/+51 l5 (a-methyl-B-hydroxy-phenp.o. i.v.

ethylamino)-propionitrile 5.0 +142 180 0/0 3-(2',3',4'-trimethoxy- 5.0 +228 30 +47 3 +24l+25 l3 benzoyl)-2-(a-methyl-B- 1.4 i.v.

hydroxy-phenethylamino)- p.o. 10.0 +173 50 +200 50 +38/+26 l8 propionitrile i.d.

3-(2',4',6'-trimethoxy- 5.0 +271 +96 12 +5/l4 8 benZQyU-Z-(a-methyI-B- 0.043 i.v.

hydroxy-phenethylamino)- i.v. 10.0 +44 +75 16 -3/14 7 propionitrilc hydrochloride i.d.

benzoyl)-2(amethyl-B- 5.0 +121 38 +34 14 +l8/+40 hydroxy-phenethylamino)- i.v.

propionitrile-hydrochloride 3-(4'-chlorobenzoyl)-2- 3.0 +278 24 +25/+62 l4 (wmethyl-B-hydroxy-pheni.v.

ethylamino)-propionittile- 7.0 +133 18 0/0 hydrochloride i.d.

(a-methyl-fl-hydroxy-phen- 2.0 +205 19 +106 42 +127/+l52 ethylamino)propionitrilei.v.

hydrochloride (a-methyl-B-hydroxy- 2.0 14 l1 l0 +25l+50 l7 phenethylamino)-pt'opioi.v.

nitrile-hydrochloride trimethoxy-phenethyl- 1.V.

amino)-propionitrilehydrochloride 3-(2',3',4'-trimethoxy- 0.2 10.0 +212 56 +31 23 +31/+22 7 trimethoxyanilinoycan bonylmethyl-piperazinyl- 1.0 10.0 +75 30 +8 20 +2ll+5 20 (1'-)]-propionitrilep.o. i.d.

dihydrochloride dimethoxybenzyH-pipei.v.

razinyl (l)]-propionitrile-dlhydrochloride comparative substance: 10.0 0 0 0 0 0 0 cinnarizine i.d.

The following examples are given for the purpose of a better understanding of the nature and the objects of this invention. The temperatures are given in degrees Centigrade.

Example 1:

2.87 g. p-chlorobenzoylacrylonitrile (formula: C1- Q CO- CH= QHC=N) are dissolved in 30 c.c. dioxane, 2.27 g. norephedrin are added, the reaction mixture is completely dissolved with gentle heating and then allowed to stand for 48 hours at room temperature. Subsequently, it is concentrated in vacuo. The residue obtained is a dark colored oil which solidifies zene, a solution consisting of 3.8 g. trimethylammonium chloride in 4 c.c. water is added and a further solution consisting of 7 'g. KCN in 36 c.c. water is added dropwise while cooling with ice and stirring. The reaction mixture is then heated to room temperature,

stirred for another hours, the benzene phase is separated and the aqueous phase is extracted twice with benzene. The combined benzene phases are washed once with water, dried with Na SO and concentrated 10 in vacuo. By recrystallization of the muddy residue from ligroin one obtains the pchlorobenzoylacrylonitrile having a melting point of 144l46.

Analysis: (cw m i z zl calculated: C 66.6 H 56 N 8.2 found: 66.3 5.5 8.0 Yield: 2.9 g. 56.5% of the theoretical calculated: C 62.6 found: 63.0 3.5 Yield: 7.9 g. 59.4% of the theoretical The p-chlorobenzoylacrylonitrile required as starting material may be prepared as follows:

Analogously to the description given hereinbefore it is possible to prepare, for instance, the following benzoylacrylonitriles:

@wo-crpcH-czn Melting Point Boiling Point A solution consisting of 14 g. p-chlorobenzoylvinylchloride in 105 c.c. anhydrous acetone is admixed with The p-chlorobenzoylvinylchloride required for the preparation of p-chlorobenzoylacrylonitrile may be obstirring' at --3S with 7 c.c. trimethylamine. While stirring, the solution is allowed to reach room temperature, then the reaction mixture is sucked off from the tained with good yields according to N. Kochetkov (Zh. Obsch. Khim. 26, page 595 (1956)) by addition of p-chlorobenzoylchloride on acetylene. Analogously,

separated precipitate and washed with anhydrous acef install?! the l ing y l rides ay be P tonc. The dry product is then suspended in c.c. benpared M lting Point Boiling Point Example 2:

3.09 g. 2-[piperazinyl(1)]-acetic acid-3,4',5- trimethoxyanilide are dissolved in 50 c.c. dioxane, 2.66 g. 2,3',4'-trimethoxybenzoylacrylic acid are added and the mixture is stirred for 30hours at 70. The separated precipitate is sucked off, washed first. with dioxane, then thoroughly with water, dried and finally boiled with 75 c.c. alcohol. The residue thus obtained is the 3-[2,3,4'-trimethoxybenzoyl]-2-[4-(3,4',5'- trimethoxyanilino)-oxoethyl-piperazinyl( 1 )]-propionic acid.

Melting point: 169

Analysis: (C H N O calculated: C 58.4 H 6.4 N 7.3 found: 58.1 6.4 7.4 Yield: 3 g. 52% of the theoretical The same product is obtained by treating N-[2- (2',3 ,4-trimethoxybenzoyl)- l -cyanoethyl]-N -(acet- 3 ',4',5 '-trimethoxy-anilido)piperazine-hydrochloride (prepared by addition of 2-[piperazinyl( l )]-acetic acid-3,4',5-trimethoxyanilide on 2',3,4'-trimethoxybenzoylacrylonitrile analogously to the prescription of Example 5, melting point: 181) with concentrated sulfuric acid. The acid may be converted with an equimolar amount of sodium ethylate to its sodium salt.

Melting point: 250 dec.

The 2',3,4'trimethoxybenzoylacrylic acid required as starting material may be prepared as follows:

4.5 g. 2',3',4trimethoxybenzoyl-acrylic acid amide are dissolved with stirring in 34 c.c. concentrated sulfuric acid. The mixture is cooled down to an internal temperature of 45, 3.55 g. NaNO are added and then c.c. water are slowly added dropwise with stirring, whereby the temperature rises to 10. Subsequently, a further 51 c.c. water are added dropwise in such a manner that finally the temperature reaches +3 and stirring is continued for another 90 minutes at room temperature. The reaction mixture is then sucked off, the residue is washed with water, dissolved in soda solution of 10%, filtered off from a slightly turbid mass and the filtrate is acidified with hydrochloric acid of 10%. Obtained is an oily precipitate which solidifies after a short while. The reaction product is sucked off, washed with water and dried, then dissolved with gentle heating in toluene and filtered off from a minor residue. The filtrate is admixed with petroleum ether and the separated precipitate is sucked off. Obtained is the 2',3',4'- trimethoxybenzoylacrylic acid.

Melting point: 89-90 Analysis: (C H O calculated: C 58.6 H 5.3 O 36.1 found: 58.7 5.2 37.2 Yield: 3.3 g. 73% of the theoretical The 2-[piperazinyl( l )l-acetic acid-3,4,5'-trimethoxyanilide which is also required as starting material may be prepared as follows:

18.3 g. 3,4,5-trimethoxyaniline and 10.1 g. triethylamine are dissolved in 300 c.c. anhydrous dioxane, 1 1.3 g. chloroacetylchloride are added at 20 with stirring and the reaction mixture is stirred for 16 hours at room temperature. It is then sucked off from the separated triethylammonium chloride, the filtrate is evaporated in vacuo, the residue is treated with ether and sucked off.

Obtained are 23 g. N-chloroacetyl-3',4,5'- trimethoxyaniline having a melting point of 103.

A solution consisting of 27 g. piperazine in c.c. isopropanol is admixed, while stirring at room temperature, with a solution consisting of 14 g. N-chloroacetyl- 3,4',5-trimethoxyaniline in 60 c.c. dioxane. The reaction solution is then heated for 7 hours under reflux, evaporated and the residue is dissolved in 2N sodium hydroxide solution and chloroformwThe chloroform phase is separated, the aqueous phase is again extracted with CHCl both chloroform extracts are combined, washed and concentrated in vacuo. The remaining oil solidifies by the addition of diisopropylether. Obtained are after suction-filtration 15 g. 2- [piperazinyl(1)]-acetic acid-3 ",4',5 '-trimethoxyanilide having a melting point of Example 3:

2 g. 3methoxybenzoylacrylonitrile are dissolved in 30 c.c. dioxane, 1.39 g. N-hydroxyethylpiperazine are added and the solution is first allowed to stand for one hour at room temperature and then concentrated in vacuo. The residue is recrystallized from benzene/petroleum ether. Obtained are 3.2 g. N-[Z-(mmethoxybenzoyl)-1cyano-ethyl]-N-[hydroxyethyl]- piperazine having a melting point of 126128.

3.2 g. of the hydroxyethylpiperazine are dissolved in 40 c.c. dioxane, 1.03 g. triethylamine are added and, at room temperature, a solution consisting of 2.33 g. 3,4,- 5trimethoxybenzoylchloride in 15 c.c. dioxane is added dropwise while stirring. Subsequently, the reaction mixture is stirred for another 16 hours at room temperature. A further 0.54 g. triethylamine as well as a solution consisting of 1.14 g. 3,4,5-trimethoxybenz oylchloride in dioxane are added and this mixture is again stirred for 16 hours at room temperature. After sucking off, the filtrate is concentrated in vacuo, the residue is dissolved in ethanolic hydrochloric acid and admixed with ether. The precipitate obtained is a slightly muddy hydrochloride. After conversion to the base and subsequent reconversion to the hydrochloride one obtains the N-[2-(m-methoxybenzoyl-l-cyanoethyl]-N-[3',4,5'trimethoxybenzoyloxyethyl]- piperazine-dihydrochloride in the form of crystals melting at 146.

Analysis: (C z a 'l) calculated: C 55.5 H 6.0 N 7 2 found: 55.0 6.1 7 1 Yield: 2.9 g. 53% of the theoretical The 3'-methoxybenzoylacrylonitrile required as i solved in 40 c.c. dioxane, 1.14 g. norephedrin are 38.9 g. of the sodium salt of the 3'-methoxybenzoylvinyl alcohol.

24.2 g. of the sodium salt are suspended in 80 c.c. benzene. Subsequently, 100 c.c. water and 60 c.c. sulfuric acid of 10% are added and the mixture is vigor- 5 ously stirred. When it is completely dissolved, the benzene layer is separated and the aqueous phase is extracted twice with benzene.

The combined benzene extracts are then gently heated under reflux with 15.4 g. thionylchloride, the excess thionyl chloride and the benzene are then distilled off in vacuo and the residue is fractionated in vacuo.

Obtained is the 3'methoxy-benzoylvinylchloride.

@co-cawca-c Melting point Melting point: ISO-152 Analysis: (C H NO calculated: C 58.9 H 5.7 N 5.3 found: 58.2 5.5 5.2 Yield: 6.5 g. 76% of the theoretical Example 5:

8.8 g. 3',4',5'-trimethoxybenzoylacrylonitrile and 11 g. 2-[piperazinyl( l )]-acetic acid-3 ',4,5 trimethoxyanilide are stirred for 7 hours at 70 in 120 c.c. dioxane. The solution is then cooled down to room temperature, filtered off from residual parts, if any, and the filtrate is evaporated in vacuo. The oily residue is dissolved in little anhydrous dioxane, admixed with Boiling point 4-CH C H 4-cH o-2, 3-Cl C H 72-74. 3 4? 5' 33 3 -6 2 '2 4, sc11 6) $42 112. 7a-e'o Example 4: A

2 g. 2,3',4'-trimethoxybenzoylacrylamide are dis- 45 added and the mixture is stirred for 20 hours at room temperature, then heated during one hour at 80 and the solution is concentrated in vacuo. The remaining oil solidifies when it is treated with ether. The residue is sucked off, washed with ether, then dissolved in warmed ethyl acetate and the filtrate is admixed with petroleum ether whereby a precipitate is formed which crystallizes after a short while. It is sucked off and the residue is washed with petroleum ether.

Thus obtained is the N-[2-(2',3',4- trimethoxybenzoyl)-l-carbonamido-ethyllnorephedrin.

Melting point: 105 1 Analysis: (cnHga z a) calculated: C 63.5 H 6.7 N 6.7 0 23.! found: 63.4 7.1 6.4 23.5 Yield: 2.l g. 67% of the theoretical The 2',3',4'-trimethoxybenzoylacrylic acid amide required as starting material may be prepared as followsr 8 g. 2',3,4'-trimethoxybenzoylacrylonitril are dissolved in 40 c.c. concentrated sulfuric acid and heated etheric hydrochloric acid, and the precipitate is sucked off and washed several times with ether. Subsequently, it is treated with water, whereby first muddy mass is formed which solidifies while further standing. The solid product is sucked off, suspended in dilute soda solution and immediately extracted three times with chloroform. The chloroform solution is washed with water, dried and concentrated in vacuo. The resinous residue is dissolved in anhydrous dioxane, admixed with etheric hydrochloric acid and the separated precipitate is sucked off and washed with ether. The residue is then stirred for one hour in about 30 c.c. water, whereby first a muddy mass is again formed which solidifies after a short while. After sucking off and recrystallizing from alcohol, one obtains the N-[2-(3',4',5'- trimethoxybenzoyl)-1-cyanoethyl]-N '-(acet-3 ,4 ',5

trimethoxyanilido)-piperazinehydrochloride.

Melting point: 178

Analysis (C l-l chNp calculated C 56.7 H 6.2 CI 6.0 N 9.4 found: 56.8 6.4 5.8 9.6

Analogously to the description given in Examples 1 5 the following compounds of the present invention may be obtained:

2, 3,4- (CH O) C CN N N-CH CO What we claim is:

1. Derivative of the 3-benzoyl-2-(B- hydroxyphenethyl-amino)-propionitrile having the formula CN R4 OH and its pharmaceutically acceptable acid addition salts, wherein R stands for a member selected from the group consisting of hydrogen and methyl, and the nucleus l may have 1 3 substituents selected from the group consisting of mono, diand tri-methoxy, monomethyl, mono-ethyl and mono-chlorine.

Melting point 142 hydrochloride hydrochloride hydroxy-phenethylamino)-propionitri1e and pharmaceutically acceptable acid addition salts thereof.

5. 3-(3',4,5'-trimethoxy-benzoyl)-2-(a-methyl-B- hydroxy-phenethylamino)-propionitrile, and pharmaceutically accceptable acid addition salts thereof.

3-(4'-methylbenzoyl)-2-(a-methyl-B- hydroxyphenethylamino )-propionitrile and pharm aceutically acceptable acid addition salts thereof. 

1. DERIVATIVE OF THE 3-BENZOYL-2-(B-HYDROXYPHENETHYLAMINO)-PROPIONITRILE HAVING THE FORMULA
 2. 3-(3''-methoxybenzoyl)-2-( Alpha -methyl- Beta -hydroxyphenethylamino)-propionitrile and pharmaceutically acceptable acid addition salts thereof.
 3. 3-(4''-chlorobenzoyl)-2-( Alpha -methyl- Beta -hydroxy-phenethylamino)-propionitrile and pharmaceutically acceptable acid addition salts thereof.
 4. 3-(2'',3'',4''-trimethoxy-benzoyl)-2-( Alpha -methyl- Beta -hydroxy-phenethylamino)-propionitrile and pharmaceutically acceptable acid addition salts thereof.
 5. 3-(3'',4'',5''-trimethoxy-benzoyl)-2-( Alpha -methyl- Beta -hydroxy-phenethylamino)-propionitrile, and pharmaceutically accceptable acid addition salts thereof.
 6. 3-(4''-methylbenzoyl)-2-( Alpha -methyl- Beta -hydroxyphenethylamino)-propionitrile and pharmaceutically acceptable acid addition salts thereof. 